The rescue effect of 15-deoxyspergualin on intraperitoneal microencapsulated xenoislets

Because the development of surface neogrowth composed mainly of macrophages and fibroblasts precedes the recurrence of hyperglycemia in treated diabet ic animals, the pericapsular macrophages may adversely affect the graft fun ction of IP alginate-poly-L-lysine-alginate (A-P-A) microencapsulated islet s. In order to clarify the role of pericapsular macrophages on late islet x enograft dysfunction, we investigated whether 15-deoxyspergualin (15-DSG), a macrophage inhibitor, has a rescue effect on the recurrent hyperglycemia in streptozotocin-induced diabetic mice that had been treated with IP trans plantation of A-P-A microencapsulated rat islets. The mean duration of norm oglycemia (whole blood glucose level below 8.3 mmol/l) in streptozotocin-in duced diabetic mice treated with implantation of about 2200-2400 of A P-A m icroencapsulated rat islets was 75 days. When the blood glucose levels were higher than 11.1 mmol/l for two consecutive determinations, 15-DSG at a do se of 0.625 mg/kg body weight or isotonic sodium chloride solution (control group) was given daily SC. The blood glucose levels decreased significantl y from 13.9 +/- 0.5 mmol/l to 11.0 +/- 1.3 mmol/l (n = 18, p < 0.05) at the fourth day and to 7.6 +/- 1.0 mmol/l (n = 18) at the 14th day of 15-DSG ad ministration. That was not significantly different from the mean glycemic l evel during the normoglycemic period (7.6 +/- 1.0 vs. 7.0 +/- 1.7 mmol/l, n = 18, p = NS). Isotonic sodium chloride solution injections did not reduce glycemic levels of mice in the control group. As another control, 10 strep tozotocin-induced diabetic mice were given the same daily doses of 15-DSG f or 14 days. 15-DSG did not decrease the blood glucose levels of diabetic mi ce in the control group. We further studied the effect of 15-DSG on the exp ression of interleukin-1 beta (IL-1 beta) in peritoneal exudate mononuclear cells (PEMCs) using reverse transcription-polymerase chain reaction. It wa s found that the mRNA of IL-1 beta was undetectable in PEMCs of 15-DSG-trea ted diabetic mice even after those cells were stimulated by lipopolysacchar ides in vitro. Administration of 15-DSG at a daily dose of 0.625 mg/kg body weight from the 22nd to the 28th day after transplantation and 7 consecuti ve days every 3 weeks thereafter did not prolong graft survival of IP micro encapsulated rat islets. Our data suggest that 15-DSG has a rescue effect w hen A-P-A microencapsulated islets have induced cellular overgrowth that th reatens the survival of the graft. It is possible that the surface overgrow th composed of macrophages is involved in the pathophysiology of late failu re of A-P-A microencapsulated xenogeneic islets.